Sickle cell disease renal manifestations

Dr m.s forghani MD, MUK

Overview of SCD

• SCD is one of the most frequent hereditary haematologic diseases in the world.

• Its most severe and common form, sickle cell anaemia (SCA), results from homozygosity for the mutant form of the gene that encodes β‑globin.

• SCA is also the most severe form of SCD in terms of its renal manifestations.

• there are 5 variants of SCD that known as Cameroon, Senegal, Benin, Bantu, and Saudi-Asian.

• Their clinical importance is because some are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease.

• These renal manifestations are generally less severe in the double heterozygous forms and SCT

pathobiology of sickle cell disease

In kidney medulla Hb S polymerization is governed by low PH , low PO2, high Osmolality

Abnormal S-RBC membrane Adhesion receptorVasa recta Low blood flow

increase RBC adhesion to the endothelium

Renal vasculopathy in SCD

Glomerular hyperfiltration

• This finding indicates that (Increase RPF, RBF,GFR) glomerular hyperfiltration is driven by increased glomerular perfusion and increased effective glomerular filtration surface area, but not by increased glomerular capillary hydrostatic pressure.

• The investigators found significantly increased GFR and renal plasma flow in patients with sickle cell disease versus controls, with a decrease in filtration fraction (FF), which suggests predominant dilatation of the efferent arteriole and loss of juxtamedullary nephrons

Acute kidney injury

• AKI occurs in 4–10% of hospitalized patients with SCD, and is more frequent in patients with acute chest syndrome (13.6%) than in patients with painful crisis (2.3%).

• AKI is prognostically important in SCD, as it predicts a less favourable outcome among patients who are transferred to the intensive care unit.

Pathogenesis of SCNIncreased renal growth Increased Na delivery, Na reabsorption, increased PCT metabolic

function (renal enlargement)Glomerular and other histologic lesionsCapillary congestion, mesangial proliferation, glomerulosclerosis,

interstitial nephritis and fibrosisProteinuria 27% of patients in the first three decades, nephrotic syndrome in

4%, Albuminuria levels >500 mg/g creatinine are associated with progressive CKD

Chronic kidney disease: 29-42%vascular, endothelial, tubular, interstitial process interactionsCKD risk factors: PB19, HTN,Hb level, age, PAH

Renal manifestations of sickle cell diseaseHaemodynamic glomerular injury

Endothelium–podocyte/pericyte crosstalk

Haemolysis-induced renal injury Urinary concentration defect Hematuria Distal nephron dysfunction

Podocyte integrityis critically dependent upon a healthy glomerular endothelium Podocyte : VEGF ---> NO SFLT1 => Inhibit trophic effect of VEGF on podocyte Endothelium : ET-1, TNF => induced podocyte dysfunction and proteinuria Endothelial dysfunction: induced procuagolant, poinflammatory phenotype and

might perturb the behaviour of pericytes

increases wall tension , Increased wall tension might damage the glomerular endothelium, the podocyte, and the filtration barrier, areas of the glomerular basement membrane will be bereft of podocyte foot processes => FSGS

Haemolysis-induced renal injury

• HbS is an unstable protein that undergoes autoxidation and denaturation to produce oxidants and free haem

• Epithelial IRON accumulation

• Heme triggers TLR4 (mesangial, endothelial, epithelial, podocyte) signaling leading to endothelial cell activation ( proinflammatory and progoagulant phenotype)

• free haem and Hb S: promotes proliferation of smooth muscle cells , proinflammatory and profibrogenic gens upregulation in tubulointerstitial and glomerular compartment

Urinary concentration defect& HematuriaPartial Distal RTA in 40% case of SCD

Treatment: Hematuria

Hematuria:

• is a common complication of SCN and often self limited in nature. Conservative measures such as bed rest, to prevent dislodging of blood clots, and oral hydration are the preferred treatments.

• Severe cases have been treated with urine alkalinization, to increase urine flow, and blood transfusion to reduce the hemoglobin S concentration.

Treatment: Proteinuria • Proteinuria and hypertension should be controlled• A patient with proteinuria should be started on ACE

inhibitor or ARB, as it can reduce protein excretion by as much as 50%.

• The blood pressure goal in a patient with proteinuria is less than 130/80mmHg.

• In SCD patient should avoid the use of diuretics as they can contribute to intravascular volume depletion and cause a sickling crisis.

• The addition of hydroxyurea to ACE inhibitoror ARB therapy might aid in reduction of proteinuria as well.

• NSAIDs should also be avoided as they can reduce the renal blood flow and depress the GFR.

Treatment : Anemia• Treatment of anemia is common in all chronic kidney

disease patients; however, those with SCD have a lower goal hemoglobin level.

• Recommendations are to keep hemoglobin levels no higher than10g/dL an davoid a hematocrit rise of greater than 1–2% per week. Higher levels of hemoglobin can precipitate a vasoocclusive crisis.

• Sickle cell patients often require blood transfusions to maintain this hemoglobin level.

• The use of erythropoietin is not routine in ESRD sickle cell patients, as it does not have the benefit of increasing the proportion of healthy hemoglobin A as a blood transfusion does.

ESRD

• The incidence of dialysis-related complications is no higher in SCD patients than in other ESRD patients.

• After 2 years of hemodialysis, SCD patients and non SCD patients have “similar rates of mortality” (33%vs.37%,respectively).

• However, patients with and without SCD on hemodialysis showed decreased “survival rates” in the SCD patients at both 3 years and 5 years (60%vs.80%at3yearsand40%vs.60%at5years).

Kidney transplantation

• The 1-year acute rejection rate and graft survival seen in SCD patients were not significantly different from those receiving kidney transplant for other causes of renal failure.

• However, the 3-year rates did show a decline in graft survival in sickle cell patients (48%vs.60% when compared with ethnically matched kidney recipients).

• The overall survival is also lower than the general population at both 1 year (78%vs.90%) and 3 years (59%vs.81%).

• Some authors have noted an increase in the frequency of painful sickle cell crisis after transplantation likely due to the subsequent rise in hemoglobin post-transplant.